It was first observed that the in vivo injection of plasmid DNA into muscle enabled the expression of foreign genes in the muscle (Wolff et al. Direct gene transfer into mouse muscle in vivo. Science 1990; 247:1465-1468.). Since that report, several other studies have reported the ability for foreign gene expression following the direct injection of DNA into the parenchyma of other tissues. Naked DNA was expressed following its injection into cardiac muscle (Acsadi et al. Direct gene transfer and expression into rat heart in vivo. The New Biologist 1991, 3(1), 71-81), pig epidermis (Hengge et al. Nature Genetics 1995, 10:161-166), rabbit thyroid (Sikes et al. Hum. Gene Ther. 1994, 5, 837), lung by intratracheal injection (Meyer et al. Gene Ther. 2, 450, 1995), into arteries using a hydrogel-coated angioplasty balloon (Riessen et al, Human Gene Ther. 1993, 4, 749; Chapman et al. Circ. Res. 1992, 71, 27), melanoma tumors (Vile et al. Cancer Res. 1993, 53, 962) and rat liver (Malone et al. JBC 1994, 269:29903-29907; Hickman Human Gene Therapy 1994, 5:1477-1483).
Another important target tissue for gene therapy is the mammalian liver, given its central role in metabolism and the production of serum proteins. A variety of techniques have been developed to transfer genes into the liver. Cultured hepatocytes have been genetically modified by retroviral vectors (Wolff et al. PNAS 1987, 84:3344-3348; Ledley et al. PNAS 1987, 84:5335-53397) and re-implanted back into the livers in animals and in people (Chowdhury et al. Science 1991, 254, 1802; Grossman et al. Nature Genetics 1994, 6, 335). Retroviral vectors have also been delivered directly to livers in which hepatocyte division was induced by partial hepatectomy (Kay et al Hum Gene Ther. 1992, 3:641-647; Ferry et al. PNAS 1991, 88:8377-8381; Kaleko et al. Hum Gene Ther. 1991, 2:27-321). The injection of adenoviral vectors into the portal or systemic circulatory systems leads to high levels of foreign gene expression that is transient (Stratford-Perricaudet et al. Hum. Gene Ther. 1990, 1, 241; Jaffe et al. Nat. Genet. 1992, 1, 372; Li et al. Hum. Gene Ther. 1993, 4, 403). Non-viral transfer methods have included polylysine complexes of asialoglycoproteins that are injected into the system circulation Wu et al. J. Biol. Chem. 1988, 263:14621-14624).
Foreign gene expression has also been achieved by repetitively injecting naked DNA in isotonic solutions into the liver parenchyma of animals treated with dexamethasone (Malone et al. JBC 1994, 269:29903-29907; Hickman Human Gene Therapy 1994, 5:1477-1483). Plasmid DNA expression in the liver has also been achieved via liposomes delivered by tail vein or intraportal routes (Kaneda et al. J. Biol. Chem. 1989, 264:12126-12129; Soriano et al. PNAS 1983, 80:7128-7131; Kaneda et al. Science 1989, 243:375-378).
Despite this progress, there is still a need for a gene transfer method that can efficiently and safely cause the expression of foreign genes in the liver in a and/or repetitive manner.